The abuse of narcotic drugs alone in the U.S. is presently an enormous and growing problem. The recent increasing appearance of fentanyl-heroin combinations is greatly exacerbating the overall problem and has resulted in an increasing number of fatal narcotic overdoses. In 2014, there were 29,467 narcotic overdose deaths approximating the number of motor vehicle fatalities in the U.S. In addition, as controls on prescription narcotics are tightened many dependent users are turning to the much cheaper (per dose) heroin and fentanyl. The appearance of designer fentanyl-related narcotics produced by Asian criminal groups attempting to circumvent controlled substance laws has become another dimension of the problem and a major concern of the Drug Enforcement Administration. These drugs exert their effects through the opioid receptor-endorphin system that consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types located in anatomically well defined areas of the mammalian CNS. Numerous endogenous opioid peptides (endorphins) function as the endogenous ligands for these receptors. This system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state. Prescription opioids, heroin, and other narcotic drugs mimic some of the actions of the natural endorphins but dysregulate the system resulting in the development of narcotic tolerance and dependence among other undesired side effects. In order to further understand the complex pharmacology of opioid drugs and develop strategies for treatment and prevention of their abuse and side effects we are pursuing several approaches. One of these is the development of an anti-heroin vaccine for the treatment and prevention of heroin abuse. A successful vaccine of this type would suppress heroin abuse and the accompanying needle sharing and spread of HIV and hepatitis. Such a vaccine should also be a valuable adjunct to prevent relapse in newly abstinent former narcotic abusers. This is an important consideration as the relapse rate for those able to quit is as high as 60% in the first year. We employed the novel approach of utilizing metabolically stable heroin-like drugs as haptens. These haptens were then covalently attached to the highly immunogenic tetanus toxoid and formulated with the Army Liposome Formulation with Aluminum. Antibody titers as high as 7 million were obtained with one of the experimental vaccines. Immunization of mice with this vaccine abolished the effect of 1 mg/kg of heroin (both by s.c and i.v. administration) in two standard assays for antinociception. This effect was undiminished 17 weeks after immunization. During this work we developed a simple nonradioactive method for the determination of the binding affinities of antibodies induced by hapten bioconjugates for drugs of abuse. We are continuing to prepare and evaluate experimental vaccines based on metabolically stable heroin-mimetic haptens.